Are we there yet? Progress toward an intervention for impairments in spatial and temporal cognition

Tony J. Simon Ph.D.MIND InstituteUniversity of California, Davistjsimon@ucdavis.eduTwitter: @22qUCDMIND

MIND INSTITUTE

Bottom Line - At the Top!

❖ Goal: create a truly evidence-based digital neurotherapeutic intervention indicated for several disorder populations

❖ Planned Deliverables: scientifically-validated, market-ready intervention & efficacy data

❖ Value: real health, not consumer/entertainment, product backed by expert clinician-scientist lab & data

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What is the Problem?

Characteristic of several neurodevelopmental disorders (NDDs): ~2 million US individuals (genetically defined NDDs) ❖ Chromosome 22q11.2 Deletion syndrome❖ Fragile X syndrome and “premutation carriers” ❖ Turner syndrome❖ Williams syndrome

Commonly reported within phenotype of ❖ Non-Verbal Learning Disorder - less clearly defined disorder

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Some brains incompletely represent spatial/temporal information

What is the Problem?

As a consequence of:❖ Healthy aging of the neurocognitive system❖ Brain injury or insult to parietal lobes/hippocampus❖ Open heart surgery repairs for congenital heart defects

❖ or possibly, cardiac defect’s effect on brain development?

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Some brains incompletely represent spatial/temporal information

What Is The Solution?

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❖ Fastbrain*, a “Digital Drug” neurotherapeutic

❖ Convergence of video game technology and two cognitive neuroscience evidence bases

Action Video Game

CognitiveEffects

Spatial /Temporal

Resolution in NDDs

Fastbrain*

*Patent pending

❖ Targeted to specific neurocognitive functions

❖ Novel proprietary algorithms adaptively titrate neurocognitive stimulation solely to individual’s spatiotemporal ability

What is the Problem?

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❖ Brain incompletely represents spatial/temporal information

❖ as in photo from 4 megapixel vs. 16 megapixel camera

❖ Features of individual units merge into others = “crowding”

❖ Hypergranularity hypothesis for NDDs - Simon, 2008

❖ loss of higher spatial and temporal frequency detection?

Fix your eyes on the cross on left. Count the bars on the right without moving eyes

Primary Patient GroupIndication: Impaired ability to mentally represent and process information about space and time.

Leads to significant functional impairments in:

❖ ability to understand quantity, learn numbers, do math, make change, tell time, learn to drive, navigate ….

❖ creates lifelong stress and anxiety, reduces employment opportunities and earnings, if not independent living

❖ individuals become lifelong consumers of, not contributors to, societal resources

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What is the Evidence?❖ Children with 22q11.2DS much less able than typically

developing peers to use attention to accurately detect objects beyond center of visual focus

Each ring is 10º more “eccentric”

from center

What is the Evidence?

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❖ When comparing a test magnitude to a fixed reference magnitude, children with 22q11.2DS require a significantly greater difference to perform as accurately as typically developing children.

❖ most TD children 80% correct at 93% vs. 87% ratio for children with 22q11.2DS, who show even greater impairment for time

What is the Evidence?❖ Children with 22q11.2DS much less able than typically

developing peers to accurately identify out-of-phase flickering target

2 4 6 8 1040

50

60

70

80

90

100Flicker Phase all groups

Accu

racy

(%)

TD22qSCA

2 4 6 8 1040

50

60

70

80

90

100Flicker Phase all groups

Accu

racy

(%)

TD22qXXXXXY

Flicker PhaseXXX (n=14) XXY (n=13) 22q (n=58) TD (n=39)

TD=39 22q=58 SCA=27

Hz

What Is The Solution?

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❖ Fastbrain is a digital neurotherapeutic

❖ Uniquely translates action video gaming “active compound” into treatment

❖ Many studies show enhanced spatial/temporal resolution in serious action gamers (VGP) and trained non-gamers

❖ No such change results from non action game types (e.g. Tetris)

Green & Bavelier. Nature, 2003

enhanced allocation of spatial attention over the visual field, even atuntrained locations, in VGPs.

The three experiments described so far indicated that video-gameplaying enhances the capacity of visual attention and its spatialdistribution. We next examined the temporal characteristics ofvisual attention and asked whether the pressure to act rapidly onseveral visual items, which is inherent to most action games, alters

the ability to process items over time, particularly the ability toavoid ‘bottlenecks’ of attention that often occur in temporalprocessing. The experimental paradigm that we used to test thetemporal aspects of visual attention is the attentional blink task (refs20–22 and Fig. 4a). Attentional blink refers to the phenomenawherein subjects have difficulties reporting a second target when itappears a few hundreds of milliseconds after the onset of a firsttarget. In our case, we used a variant of the attentional blink, inwhich participants were asked to identify a first target and thendetect a second target. This task includes two distinct attentionalbottlenecks. First is the attentional blink per se, which is thedifficulty of processing a second target that comes 200–500msafter the onset of the first one. Second is the cost of switchingtasks between the first and second target (from identification todetection); unlike the attentional blink per se, this effect is mostpronounced when the two targets are temporally adjacent and thendecreases slowly as the time between the two targets increases. Thisattentional bottleneck is not specific to vision but rather appearsamodal21,23,24. Thus, by using an identification/detection attentionalblink task, we could test whether the enhanced capacities aftervideo-game training not only applied to a purely visual bottleneckbut also generalized to an amodal one.

Figure 2 Enumeration performance. When asked to report the number of squares brieflyflashed, VGPs were able to apprehend more items at once than were NVGPs (4.9 versus

3.3). Overall, VGPs were significantly more accurate than NVGPs (78% versus 65%,

P , 0.003) and, as expected, this difference only emerged for numbers above the

subitizing range of NVGPs. Error bars denote s.e.m. (*P , 0.05, **P , 0.01).

Figure 3 Measure of attention over space. a, Sequence of displays in the useful field ofview task. Participants indicated the spoke on which the small target (triangle within circle)

appeared. By presenting the target at different eccentricities, this task affords an

opportunity to test the spatial distribution of visual attention. b, Localization accuracy.VGPs showed large enhancements in localization ability at all eccentricities. The

superiority of VGPs at 308 indicates that the enhancement of spatial attention observed in

this population is not limited to trained locations. Error bars denote s.e.m. (**P , 0.01).

Figure 4 Measure of attention over time. a, Attentional blink task. Black letters wererapidly presented at fixation in a standard rapid, serial, visual presentation manner. At a

random time in the stream, a white letter was presented (first target). After this first target,

an ‘X’ (second target) was presented among the following letters 50% of the time. After

the trial, the subject gave the identity of the first target and then indicated whether the ‘X’

was presented. Of interest is the performance of subjects on the ‘X’ detection task, given

that they have correctly identified the white letter. b, Attentional blink performance. Atearly lags, VGPs performed better (less blink) than NVGPs; as lag increased, the effect of

the attentional bottlenecks decreased and, as expected, the two populations became

comparable (lag by population P , 0.02). Error bars denote s.e.m. Points without error

bars indicate that the s.e.m. was smaller than the size of the square (**P , 0.01).

letters to nature

NATURE |VOL 423 | 29 MAY 2003 | www.nature.com/nature 535© 2003 Nature Publishing Group

enhanced allocation of spatial attention over the visual field, even atuntrained locations, in VGPs.

The three experiments described so far indicated that video-gameplaying enhances the capacity of visual attention and its spatialdistribution. We next examined the temporal characteristics ofvisual attention and asked whether the pressure to act rapidly onseveral visual items, which is inherent to most action games, alters

the ability to process items over time, particularly the ability toavoid ‘bottlenecks’ of attention that often occur in temporalprocessing. The experimental paradigm that we used to test thetemporal aspects of visual attention is the attentional blink task (refs20–22 and Fig. 4a). Attentional blink refers to the phenomenawherein subjects have difficulties reporting a second target when itappears a few hundreds of milliseconds after the onset of a firsttarget. In our case, we used a variant of the attentional blink, inwhich participants were asked to identify a first target and thendetect a second target. This task includes two distinct attentionalbottlenecks. First is the attentional blink per se, which is thedifficulty of processing a second target that comes 200–500msafter the onset of the first one. Second is the cost of switchingtasks between the first and second target (from identification todetection); unlike the attentional blink per se, this effect is mostpronounced when the two targets are temporally adjacent and thendecreases slowly as the time between the two targets increases. Thisattentional bottleneck is not specific to vision but rather appearsamodal21,23,24. Thus, by using an identification/detection attentionalblink task, we could test whether the enhanced capacities aftervideo-game training not only applied to a purely visual bottleneckbut also generalized to an amodal one.

Figure 2 Enumeration performance. When asked to report the number of squares brieflyflashed, VGPs were able to apprehend more items at once than were NVGPs (4.9 versus

3.3). Overall, VGPs were significantly more accurate than NVGPs (78% versus 65%,

P , 0.003) and, as expected, this difference only emerged for numbers above the

subitizing range of NVGPs. Error bars denote s.e.m. (*P , 0.05, **P , 0.01).

Figure 3 Measure of attention over space. a, Sequence of displays in the useful field ofview task. Participants indicated the spoke on which the small target (triangle within circle)

appeared. By presenting the target at different eccentricities, this task affords an

opportunity to test the spatial distribution of visual attention. b, Localization accuracy.VGPs showed large enhancements in localization ability at all eccentricities. The

superiority of VGPs at 308 indicates that the enhancement of spatial attention observed in

this population is not limited to trained locations. Error bars denote s.e.m. (**P , 0.01).

Figure 4 Measure of attention over time. a, Attentional blink task. Black letters wererapidly presented at fixation in a standard rapid, serial, visual presentation manner. At a

random time in the stream, a white letter was presented (first target). After this first target,

an ‘X’ (second target) was presented among the following letters 50% of the time. After

the trial, the subject gave the identity of the first target and then indicated whether the ‘X’

was presented. Of interest is the performance of subjects on the ‘X’ detection task, given

that they have correctly identified the white letter. b, Attentional blink performance. Atearly lags, VGPs performed better (less blink) than NVGPs; as lag increased, the effect of

the attentional bottlenecks decreased and, as expected, the two populations became

comparable (lag by population P , 0.02). Error bars denote s.e.m. Points without error

bars indicate that the s.e.m. was smaller than the size of the square (**P , 0.01).

letters to nature

NATURE |VOL 423 | 29 MAY 2003 | www.nature.com/nature 535© 2003 Nature Publishing Group

❖ Medications alter levels of target across entire brain

❖ Targets need instead to be specific circuits & functions

❖ Cannot train whole brain

❖ Most “brain training” creates non-transferrable practice

Digital Neurotherapeutics - Better Targeted?

Digital vs Pharma Neurotherapeutics❖ Behavior change is target outcome, possible with digital

alone

❖ Pharma alone may well be only half the intervention

❖ e.g. failed trials of FXS drugs like mGluR inhibitors

❖ not solely due to differential responders

❖ “what fires together wires together” won’t happen without targeted behavioral intervention

❖ Better outcome measured derivable from source paradigms

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Why Not Off-The-Shelf Games?❖ Many AVGs not great for cognitively impaired kids

❖ Commercial game algorithms respond to many factors

❖ adaptivity not targeted to spatiotemporal ability

❖ Instead, convert AVG active compound to health product

❖ disguised as game with commercial-level production values to ensure motivation & compliance

❖ Must be “medicine that children want to take”!

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Fastbrain Functional Prototype❖ Met our criteria for a scalable prototype

❖ Filed patent for proprietary algorithms

❖ Completed basic play testing/focus grouping

❖ played by 2 kids (7 & 8 years) from target populations

❖ both challenged but showed progress

❖ very motivated to play more

❖ Now cacheing data with IRB approval & iterating design

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Considerable work put into decisions on optimalappropriate platform and input device to best

translate science and accommodate target populations

So, Does Fastbrain Work?

❖ Current prototype only intended as proof of concept

❖ We limited the “range” & accelerated the adaptation

❖ Yet, prototype is sensitive to competence & generates change in the impaired!

❖ Shows the algorithms can achieve their stated goals!

Young adult unimpaired “gamer”

Space

Time

Spatial Extent

Temporal Rate

6 year-old impaired child

Space

Time

Does Fastbrain Induce Change?❖ To try to extend training, we

changed “consistency” parameter

❖ requires 14 of 20 correct for FOV change (from 7 of 10)

❖ AB returned 4 months later

❖ FB20 games 1 & 2 improvement slower, asymptotes similarly, increased duration

❖ possible enhanced initial ability? Does achieve longer play (i.e. training) time

Spatial Extent Temporal Rate

What’s Next?

•Pilot efficacy trial - “unfunded” project underway

• Implement functionality for larger trials/experiments

•Will require significant investment of resources

• License IP to existing entity & develop in partnership

• create start-up, raise funds, hire staff ……

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Thank you for your time!

MIND INSTITUTE

What’s The Expected Exit?

A. Initiate start-up, raise $$, develop full Fastbrain product

B. License IP to existing entity & develop in partnership

❖ “Brain health” company seeking new/more evidence-based neurotherapeutics

❖ Akili, Lumosity, LearningRx, HappyNeuron, Posit

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